Mpox outbreak in the Netherlands, 2022: public health response, characteristics of the first 1,000 cases and protection of the first-generation smallpox vaccine

In early May 2022, a global outbreak of mpox started among persons without travel history to regions known to be enzootic for monkeypox virus (MPXV). On 8 August 2022, the Netherlands reported its 1,000th mpox case, representing a cumulative incidence of 55 per million population, one of the highest cumulative incidences worldwide. We describe characteristics of the first 1,000 mpox cases in the Netherlands, reported between 20 May and 8 August 2022, within the context of the public health response. These cases were predominantly men who have sex with men aged 31–45 years. The vast majority of infections were acquired through sexual contact with casual partners in private or recreational settings including LGBTQIA+ venues in the Netherlands. This indicates that, although some larger upsurges occurred from point-source and/or travel-related events, the outbreak was mainly characterised by sustained transmission within the Netherlands. In addition, we estimated the protective effect of first-generation smallpox vaccine against moderate/severe mpox and found a vaccine effectiveness of 58% (95% CI: 17–78%), suggesting moderate protection against moderate/severe mpox symptoms on top of any possible protection by this vaccine against MPXV infection and disease. Communication with and supporting the at-risk population in following mitigation measures remains essential.

In early May 2022, a global outbreak of mpox started among persons without travel history to regions known to be enzootic for monkeypox virus (MPXV). On 8 August 2022, the Netherlands reported its 1,000th mpox case, representing a cumulative incidence of 55 per million population, one of the highest cumulative incidences worldwide. We describe characteristics of the first 1,000 mpox cases in the Netherlands, reported between 20 May and 8 August 2022, within the context of the public health response. These cases were predominantly men who have sex with men aged 31-45 years. The vast majority of infections were acquired through sexual contact with casual partners in private or recreational settings including LGBTQIA+ venues in the Netherlands. This indicates that, although some larger upsurges occurred from point-source and/or travel-related events, the outbreak was mainly characterised by sustained transmission within the Netherlands. In addition, we estimated the protective effect of first-generation smallpox vaccine against moderate/severe mpox and found a vaccine effectiveness of 58% (95% CI: 17-78%), suggesting moderate protection against moderate/severe mpox symptoms on top of any possible protection by this vaccine against MPXV infection and disease. Communication with and supporting the at-risk population in following mitigation measures remains essential.

Background
In early May 2022, the United Kingdom reported cases of monkeypox virus (MPXV) infection among people without travel history to regions known to be enzootic for MPXV such as West and Central Africa [1]. Within weeks, multiple cases were reported in Europe, North-America and Australia [2][3][4]. Unlike previous reported outbreaks of mpox in the African region and the United States, almost all cases were men who (also) have sex with men (MSM), particularly those with multiple sexual partners.

Outbreak detection
The first mpox case in the Netherlands was identified at a sexual health clinic (SHC) in Amsterdam after international alerts (EpiPulse, Early Warning and Response System) and confirmed on 20 May 2022. The Netherlands reported the 1,000th mpox case on 8 August 2022, representing a cumulative incidence rate of 55 per million population, one of the highest rates worldwide after Spain (104/million) and Portugal (69/ million) at that time, and with 31,112 confirmed mpox cases reported worldwide [5].
More than half (57%) of the Dutch population have never been exposed to orthopoxviruses and can be considered immunologically naïve, as the Netherlands stopped the first-generation smallpox vaccination campaign in 1974 and infections with orthopoxviruses are rare [6,7]. Worldwide, the World Health Organization stopped the smallpox vaccination campaign in 1977. In 1980, smallpox was declared eradicated [8]. Individuals who have been vaccinated with the first-generation smallpox vaccine (which required one dose for complete vaccination) might, however, still benefit from cross-protection against (severe) mpox through MPXVneutralising antibodies [9,10].
Here we describe the characteristics of the first 1,000 mpox cases in the Netherlands and the public health response, and we provide estimates of protection against moderate/severe mpox symptoms offered by the first-generation smallpox vaccine.

Case detection
Individuals who presented with symptoms suggestive of mpox according to the possible/probable case definition (Box 1) to an SHC or general practitioner (GP) or otherwise were referred and notified to the regional public health service (PHS) for (additional) mpox diagnostics and public health measures (see: Data Collection; Public Health Response).

Laboratory methods
The MPXV laboratory confirmation was performed on pharyngeal and/or skin lesion(s) and/or anal swabs collected either into virus transport medium or on dry or e-swabs. Samples were tested by real-time PCR. Diagnostic protocols (12 diagnostic laboratories) were validated and based either on pan-orthopox realtime PCR with subsequent MPXV detection through sequence analysis or an MPXV-specific PCR [11][12][13].

Definitions
Cases were reported as possible, probable and confirmed cases (Box 1). Their contacts were categorised as high-, medium-and low-risk exposure (Box 2). Confirmed mpox cases were categorised as mild or moderate/severe mpox to allow calculation of the vaccine effectiveness (VE) of the first-generation smallpox vaccine against moderate/severe disease. Cases with mild mpox were defined as those experiencing up to two systemic symptoms (e.g. lymphadenopathy, headache, excluding fever) and with skin lesions on up to one body location (head, limbs, oral, trunk or peri-anal/genital). Cases with moderate/severe mpox were defined as those experiencing three or more systemic symptoms (including potential fever) and/or with skin lesions on at least two body locations and/ or hospitalisation for mpox. Country of origin was categorised according to the definition from Statistics the Netherlands: the Netherlands, Türkiye, Morocco, the Netherlands Antilles, Surinam and Aruba, 'other Western' country which refers to any country on the European continent (excluding Türkiye), North-America, Oceania or Indonesia as well as Japan, and 'other non-Western' countries refers to all other countries [14]. People at high risk of MPXV exposure were defined as individuals who engaged in group sex, sex on premises (lesbian gay bisexual transgender queer intersex and asexual and other (LGBTQIA+) venues and saunas) in the Netherlands or abroad, or who were a contact of a confirmed mpox case 21 days before symptom onset.

Data collection
Data were collected as part of epidemiological routine surveillance based on obligatory notification of suspected and confirmed cases. After notification to the PHS, a public health team member contacted the case to collect information on demographics including age, sex, medical history, sexual orientation, symptoms, date of symptom onset, hospitalisation and details on source (e.g. risk behaviour and potential source(s) of infection in the 21 days before symptom onset) and contact tracing (numbers of high-, medium-and lowrisk contacts). To ensure notification of mpox cases from the PHS to the National Institute for Public Health and the Environment (RIVM), a questionnaire was included in the national surveillance system for notifiable diseases (OSIRIS) for collection of the gathered demographical, clinical and epidemiological information on cases. We extracted for analysis data on mpox cases reported to the RIVM from 20 May until 8 August 2022 from the OSIRIS database.

Statistical analysis
We described the demographical and epidemiological characteristics of mpox cases. The reporting delay (days) between symptom onset and notification as a confirmed mpox case was calculated. Based on the calculated reporting delay, we estimated the daily reported confirmed cases by date of symptom onset by correcting for under-reporting (i.e. nowcasting) [15].
The VE of the first-generation smallpox vaccine against moderate/severe mpox was calculated among individuals born before 1978 by comparing the odds of firstgeneration smallpox vaccination between persons with moderate/severe mpox and those with mild mpox. We calculated the VE as 1 minus the odds ratio (OR). The crude OR and 95% confidence intervals (CI) were calculated using logistic regression analyses. Individuals who had received Imvanex (Bacarian Nordif A/S, Kvistgård, Denmark), the third-generation smallpox vaccine approved in the European Union, as post-exposure prophylaxis (PEP) (n = 40) were excluded from VE analyses due to its likely influence on symptom development. In addition, VE was estimated adjusting for age (44-50, 51-55 and ≥ 56 years). Statistical analyses were conducted using R version 4.0.2.
The reporting delay, measured from time of symptom onset to reporting as a confirmed mpox case in OSIRIS, was on average 12 days (median: 10 days) days, with an average delay measured from symptom onset to testing and notification as a suspected case of 6 days (median: 5 days) The number of reported cases by date of symptom onset reached a peak in the first half of July 2022.
Epidemiological data on women and heterosexual men were often lacking (because of unclear exposure or unwillingness to disclose details). Of 10 women (including one transgender person), mostly detected via GP, five reported contact with a case ≤ 21 days before symptom onset. Of 19 male heterosexuals, mostly detected through SHC or GP, two reported contact with a case ≤ 21 days before symptom onset.

What did you want to address in this study?
In May 2022, a global outbreak of mpox started (unlike previous outbreaks) among people who had not travelled to regions where monkeypox virus is known to circulate. We wanted to describe the public health response in the Netherlands and the characteristics of the cases to explore which population is at highest risk. We also explored whether the smallpox vaccine available globally before 1978 protects against moderate/severe mpox symptoms.

What have we learnt from this study?
International alerts and communication to clinicians led to rapid detection of the first mpox case in the Netherlands. The vast majority of infections occurred in men who (also) have sex with men, aged 31-45 years, and were acquired through sexual contact with casual partners in private or recreational settings including LGBTQIA+ venues in the Netherlands. People vaccinated against smallpox in the 1970ies or before are likely to be protected against moderate/severe mpox symptoms.

What are the implications of your findings for public health?
There is no or little indication of transmission through other than direct (sexual) contact. International alerts are important for rapid diagnosis and response. Public health control measures and communication should be aimed at the population at highest risk, who should be included in the design of such outreach programmes. The effect of currently used smallpox vaccines, different from the old vaccine, needs to be researched.
Fifty-one per cent (425/830) reported three or more systemic symptoms, and 63% (573/912) lesions on at least two different body locations. Only 43 of 991 (4%) reported coughing and 81 of 991 (8%) other respiratory symptoms. Reporting any respiratory symptoms did not correlate with the presence of oral lesions: of cases reporting respiratory symptoms, 14% reported oral lesions compared with 11% of cases not reporting respiratory symptoms (p = 0.6). Twenty-six percent (215/833) of cases had mild mpox and 74% (711/991) moderate/severe mpox symptoms. One infection was detected in a child and details have been published [16].

Box 1
Clinical and epidemiological criteria for classification of mpox cases, the Netherlands, as at 8 August 2022

Confirmed case
A person with a laboratory-confirmed MPXV infection (PCR-positive for orthopoxvirus with or without additional MPXV confirmation by sequencing or MPXV-specific PCR).

Probable case
A person with skin lesions consistent with mpox on (a part of) the body with symptom onset after 1 March 2022, and/or with complaints consistent with proctitis (including anal pain) that occurred after 1 March 2022, and optionally one or more systemic symptoms a consistent with mpox, AND one or more of the following criteria: • contact with a confirmed or probable case of mpox 21 days before symptom onset, • a man who (also) has sex with men, • a female partner of a man who (also) has sex with men, • a person (regardless of sexual orientation) who indicates having had multiple sexual contacts, anonymous or not, or paid for (e.g. at sex parties) 21 days before symptom onset.

Possible case
A person with skin lesions consistent with mpox on (a part of) the body with symptom onset after 1 March 2022, and/or with complaints consistent with proctitis (including anal pain) that occurred after 1 March 2022, and optionally one or more systemic symptoms a consistent with mpox, AND without an epidemiological link with a person who has clinically suspected or confirmed varicella, and where an infection with another known causative agent of similar skin appearance, such as herpes zoster, (primary) herpes simplex, primary or secondary syphilis, is considered unlikely.
and moderate/severe mpox showed a VE estimate of 50% (95% CI: −10 to 78%) but with wide confidence interval due to a small sample size.

Public health response
In view of the increasing number of mpox cases in neighbouring European countries early May 2022, an mpox response team (RT) was convened on 18 May at the Centre for Infectious Disease Control (CIb) of the RIVM. The RT consisted of experts from the CIb, representatives of regional PHS, the external reference laboratory (Viroscience Erasmus Medical Centre), the medical expert working group on sexual health and STI (WASS), Soa Aids Nederland -a Dutch STI policy and prevention foundation for professionals and the public -and infectious disease specialists. The RT provided scientific advice (on request of the Ministry of Health, (MoH)) on risk assessment and classification, notifiable disease status, diagnostics, infection prevention and control measures regarding cases and contacts including risk communication and pre-and post-exposure vaccination. After the notification of the first mpox case on 20 May and on advice of the RT, the MoH declared mpox a notifiable disease in group A on 20 May. This group A status entails centralised coordination of the response and swift public health actions, including mandatory notification within 24 h by treating physicians and laboratories to the PHS of both suspected (possible/probable) as well as confirmed cases, case isolation, source and contact tracing and the ability to quarantine contacts [17]. After healthcare professionals notified a suspected case, a public health team member contacted the case to arrange diagnostic testing and advise self-isolation and hygiene measures. If mpox diagnosis was confirmed, the PHS informed and monitored high-and medium-risk contacts by telephone for development of symptoms up to 21 days after their last exposure. In addition, high-risk contacts were offered the Imvanex vaccine as PEP -preferably administered within 4 and up to 14 days after first exposure.
Initially, contacts who had sexual, intimate skin-toskin or household contact (high-risk contact; Box 2) with mpox cases were asked to self-quarantine for 21 days. However, on 24 June, a national council of experts (Deskundigenberaad) advised to replace this quarantine measure with the advice to refrain from intimate (and sexual) contact during the 21-day monitoring period. Reasons for this policy change were the increasing evidence that direct skin-to-skin or sexual contact were the dominant transmission routes and challenges during contact tracing, such as hesitancy to reveal contact information of (sexual) contacts because of the potential consequences of prolonged quarantine. A second policy change was made on 7 July, when 2-dose Imvanex vaccination schemes were offered as pre-exposure vaccination (mpox PrEP) to individuals at high risk of mpox to curb transmission. Transgender persons and MSM were eligible if they (i) received HIV PrEP (or were on a HIV PrEP waiting list) via SHC or GP, (ii) were living with HIV and screened for hepatitis C as a proxy for increased risk of STI or (iii) were known at the SHC or GP to be at increased risk of STI, including MSM sex workers [18]. Individuals who had received a first-generation smallpox vaccination in the past required only one dose of Imvanex vaccine for completion of mpox PrEP. The vaccination campaign started

Box 2
Categorisation of high-, medium-and low-risk contacts of mpox cases during the outbreak in the Netherlands, as at 8 August 2022 High-risk contact: a person with one or more of the following types of contact with an mpox case during their infectious period: • any type of sexual contact, • intensive skin-skin contact (such as hugging, kissing), • household contact, excluding intensive skin-skin contact and sexual contact, • unprotected direct contact with an mpox patient and/or contaminated patient material, • laboratory employees with unprotected exposure accident involving contaminated material.
Medium-risk contact: a person with one or more of the following types of contact with an mpox case during their infectious period • unprotected prolonged (cumulative more than 2 h) face-to-face contact within 1.5 m distance (such as caregivers without a mouth and nose mask, in social situations, including public transport).
Low-risk contact: a person with one or more of the following types of contact with an mpox case during their infectious period • unprotected short (cumulative less than 2 h) face-to-face contact within 1.5 m distance (such as caregivers without PPE), • fellow airline travellers with a journey time (more than 8 h) within 1.5 m distance (1-2 seats around the index), • social contact short (cumulative less than 2 h) face-to-face contact within 1.5 m distance.
No risk: a person with one or more of the following types of contact with an mpox case during their infectious period • caregivers (including laboratory staff) with full PPE: direct contact with an mpox patient and/or contaminated patient material, • caregivers and social contacts with unprotected exposure at more than 1.5 m distance (regardless of duration).
PPE: personal protective equipment. on 25 July in two public health regions with the highest mpox incidence (Amsterdam and The Hague), later followed by all regions in the Netherlands. Individuals who were eligible received an invitation by post and/or email, and/or telephone.

Risk communication
The RT also coordinated risk communication towards the at-risk population, professionals and the general public. The RIVM provided information on mpox to the general public (e.g. on disease characteristics, symptoms and prevention) through the RIVM website and (social) media. Professionals (e.g. medical microbiologists, infectious disease physicians, SHC and PHS professionals) were informed through the mpox guideline, and were regularly updated on clinical characteristics, (new) diagnostics, control measures and the epidemiological situation through direct messaging services [19][20][21].
Soa Aids Nederland coordinated the mpox communication campaign targeting the MSM community. Communication materials including posters, flyers and digital content were developed to improve knowledge on and raise awareness for mpox (e.g. symptoms, partner notification, self-isolation, vaccination and other riskreducing measures). These materials were distributed to all PHS, HIV treatment centres and LGBTQIA+ venues across the country, including gay clubs, saunas and other (sex) venues, and social events such as Gay Prides. LTBTQIA+ club owners and event organisers were informed about mpox, transmission risks and prevention measures (such as hygiene guidelines) for sexon-premises. A manual was developed for PHS to guide outreach control measures and to start a dialogue about mpox with the LGBTQIA+ community [22]. Online campaigns included information on mpox (prevention) on websites, Facebook and Instagram accounts from organisations targeting LGBTQIA+ communities (such as Man-tot-Man from the PHS of Amsterdam, PrEP-NU, several regional PHS website and COC the Netherlands -an organisation advocating the LGBTQIA+ rights, as well as gay-dating apps such as Grindr and Recon). Information and real-life stories were shared through podcasts. In addition, Soa Aids Nederland facilitated and provided financial support to the LGBTQIA + community to organise their own mpox webinar ('Het Grote Monkeypox Informatie Webinar' on 3 August 2022).

Discussion
We describe the mpox outbreak in the Netherlands, which was part of an international outbreak, and the Dutch public health response [2,4]  HIV: human immunodeficiency virus; NA: not applicable; PEP: post-exposure prophylaxis; PrEP: pre-exposure prophylaxis; STI: sexually transmitted infection. b Including medication against infections such as antibiotics or anti-HIV mediation, immunosuppressants, antiacids, anti-cholesterol drugs, chemotherapy, and HIV PrEP. c Other than HIV medication, such as antibiotics. d High-and/or medium-risk contact(s) within 21 days before symptom onset.

Table 1b
Demographic characteristics of laboratory confirmed mpox cases in the Netherlands, 20 May-8 August 2022 (n = 1,000) travel-related events, the outbreak was mainly characterised by sustained transmission within the country.
International alerts and communication to relevant clinicians led to rapid detection of the first mpox case in the Netherlands. A retrospective study showed no evidence of transmission before May 2022 [26]. Within 1 day of the first confirmed case, the Dutch MoH declared mpox a notifiable disease in group A. This allowed for a nationally coordinated response, notification of both suspected and confirmed cases and the ability to quarantine contacts, essential measures when aiming for disease elimination with little prior information on disease characteristics such as dominant transmission route and severity. As the outbreak continued, there was little evidence of indirect or respiratory transmission and, combined with signals from the LGBTQIA+ community on low intention to isolate/ quarantine, it was important to scale down initial stringent measures as soon as evidence allowed, to prevent potential counter-productive effects of the measures.
Although 33% of the cases reported contact with another case ≤ 21 days before symptom onset, only 6% were detected though contact tracing, and information on risk behaviour and sexual (anonymous) contacts was often lacking. Communicating with and supporting the at-risk population in following mitigation measures will therefore remain essential. Besides rapid communication efforts towards the LGBTQIA+ community, there was active involvement of e.g. gay clubs and sauna owners in developing educational materials and outreach programmes.
Previous international reports show that mpox is more severe in elderly people, pregnant women, children and immunocompromised people, with mortality rates between 1% and 10% [27,28]. In the current outbreak, with ongoing sexual person-to-person transmission, few hospitalisations and deaths have been reported internationally, and it seems that fewer than one in 1,000 cases die from mpox-related complications [27][28][29]. This difference in morbidity and mortality could c Mild mpox: cases experiencing no more than two systemic symptoms (e.g. lymphadenopathy, headache, excluding fever) and skin lesions on no more than one body location (e.g. head, limps, trunk, peri-anal/genital). Moderate/severe mpox: cases experiencing three or more systemic symptoms and/or skin lesions on two or more body locations and/or hospitalisation for mpox.

Table 2b
Clinical characteristics of mpox cases, the Netherlands, 20 May-8 August 2022 (n = 1,000) be explained by bias in the populations involved, as the current circulation is not seen in children, pregnant women and rarely in immunocompromised people, or by selection bias related to health system constraints in Africa with additionally possible overreporting of severe cases. Another reason could be the specific strain involved or differences in the mode of transmission as few cases reported respiratory symptoms (12%) and there was no or little indication of indirect transmission. LGBTQIA+: lesbian gay bisexual transgender queer intersex and asexual and other; NL: the Netherlands; NA: not applicable.
b More than one answer was possible.

Table 3b
Reported transmission routes of infection and behavioural characteristics of mpox cases, the Netherlands, 20 May-8 August 2022 (n = 1,000) We did not have adequate data to allow estimation of VE of first-generation smallpox vaccines against mpox infection. However, we found among those born before 1978 a VE of 58% (95% CI: 12-80%) against moderate/severe mpox. This suggests moderate protection against mpox symptoms on top of any possible protection by the first-generation vaccine against MPXV infection or disease.
Although only 13% of all cases had received a firstgeneration smallpox vaccine and thus no protection is expected for the majority of cases, this result can support policymakers in allocating scarce vaccines. In the Netherlands Imvanex is available as mpox PrEP for populations at high risk to prevent mpox infection and curb transmission. Those who were vaccinated with the first-generation vaccine, received only one dose of Imvanex vaccine for complete mpox PrEP rather than two. It is uncertain if our VE estimate of the first-generation smallpox vaccine is transferable to the thirdgeneration smallpox vaccine (Imvanex) presently in use. Whereas the first-generation vaccine contained infectious vaccinia virus, the third-generation vaccine contains a further attenuated, non-replicating vaccinia virus and is therefore less immunogenic than the firstgeneration vaccine [32]. A recent study suggests the third-generation vaccine induces fewer antibodies with cross-reactivity to mpox than the first-generation vaccine [10]. VE estimates of Imvanex against MPXV infection, mpox symptoms and/or duration of illness could impact public health control measures such as vaccination strategies and isolation.
There are several limitations to our study. Our data were cross-sectional and data on disease progression were not available. Also, differences in the time point of first contact with the PHS between mild and moderate/severe cases can bias VE estimates, e.g. mild cases were contacted earlier by the PHS than moderate/ severe cases, and symptoms developing after that contact might not be registered. However, within our population for VE analysis, there was no significant difference in time between symptom onset and the first PHS contact between mild and moderate/severe mpox cases: mild cases were contacted on (median) Day 6 (IQR: Day 5) and moderate/severe cases on (median) Day 5 (IQR: Day 5) after symptom onset (p = 0.28). We used self-reported vaccination status to calculate VE, potentially leading to misclassification. In addition, the classification of mild and moderate/severe disease is somewhat arbitrary and based on combined number(s) and body locations of symptoms. However, disease severity is rather subjective, and people may experience mpox disease to different extent.
Although the outbreak was still ongoing at a low level in September 2022, the number of reported cases by date of symptom onset reached a peak in the first half of July 2022. This could in part be a result of the public health control measures and of acquired immunity from natural infection or vaccination in persons with high risk of MPXV exposure. The full extent of the outbreak, including potential asymptomatic MPXV infections, may have been higher [33]. Serological population studies and case-control studies may provide additional information on the wider extent of exposure and infection.

Conclusions
The 2022 outbreak of mpox among MSM was mainly characterised by sustained transmission through direct (sexual) contact. International alerts and communication to relevant clinicians led to rapid detection of the first mpox case in the Netherlands. Individuals who received a first-generation smallpox vaccine had a lower probability of developing moderate/severe mpox. Communication with and support of the at-risk Mild mpox: cases experiencing no more than two systemic symptoms (e.g. lymphadenopathy, headache, excluding fever) and skin lesions on no more than one body location (e.g. head, limps, trunk, peri-anal/genital) only. Moderate/severe mpox: cases experiencing three or more systemic symptoms (including fever) AND/OR skin lesions on at least two body locations and/or hospitalisation for mpox. Classifications used in sensitivity analysis: Mild mpox: cases experiencing no more than two systemic symptoms (e.g. lymphadenopathy, headache, excluding fever) and skin lesions on no more than one body location (e.g. head, limps, trunk, peri-anal/genital) only. Moderate/ severe mpox: cases experiencing three or more systemic symptoms (including fever) AND skin lesions on at least two body locations and/or hospitalisation for mpox.
population in following mitigation measures will remain essential.

Funding statement
The study was funded by the Ministry of Health, Welfare and Sports.

Ethical statement
This study received medical ethical clearance (EPI-584) by the Centre for Clinical Expertise (KEC) at the RIVM.